IN VITRO SOLUBLE EPOXIDE HYDROLASE ENZYME INHIBITORY ACTIVITY OF SOME NOVEL CHALCONE DERIVATIVES

Soluble epoxide hydrolase (sEH) is an enzyme that is considered a potential therapeutic target in human cardiovascular disease. Triterpenes (1–4) and phenylpropanoids (5–10) were isolated from Lycopus lucidus to obtain sEH inhibitors through various chromatographic purificationtechniques. The isolated compounds were evaluated for their inhibitory activity against sEH, and methyl rosmarinate (7), martynoside (8), dimethyl lithospermate (9) and 9″ methyl lithospermate (10) showed remarkable inhibitory activity, with the IC50 values ranging from 10.6 ± 3.2 to 35.7 ± 2.1 µM. Kinetic analysis of these compounds revealed that 7, 9 and 10 were competitive inhibitors bound to the active site, and 8 was the preferred mixed type inhibitor for allosteric sites. Additionally, molecular modeling has identified interacting catalytic residues and bindings between sEH and inhibitors. The results suggest that these compounds are potential candidates that can be used for further development in the prevention and treatment for cardiovascular risk.

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Soluble Epoxide Hydrolase as an Important Player in Intestinal Cell Differentiation

Cells Tissues Organs ◽

10.1159/000512807 ◽

2020 ◽

Vol 209 (4-6) ◽

pp. 177-188

Author(s):

Katerina Cizkova ◽

Katerina Koubova ◽

Tereza Foltynkova ◽

Jana Jiravova ◽

Zdenek Tauber

Keyword(s):

Cell Differentiation ◽

Colorectal Carcinoma ◽

Cell Lines ◽

Epoxide Hydrolase ◽

Soluble Epoxide Hydrolase ◽

Intestinal Cell ◽

Caco2 Cells ◽

Important Player ◽

Ht 29

There is growing evidence that soluble epoxide hydrolase (sEH) may play a role in cell differentiation. sEH metabolizes biologically highly active and generally cytoprotective epoxyeicosatrienoic acids (EETs), generated from arachidonic acid metabolism by CYP epoxygenases (CYP2C and CYP2J subfamilies), to less active corresponding diols. We investigated the effect of sEH inhibitor (TPPU) on the expression of villin, CYP2C8, CYP2C9, CYP2J2, and sEH in undifferentiated and in vitro differentiated HT-29 and Caco2 cell lines. The administration of 10 μM TPPU on differentiated HT-29 and Caco2 cells resulted in a significant decrease in expression of villin, a marker for intestinal cell differentiation. It was accompanied by a disruption of the brush border when microvilli appeared sparse and short in atomic force microscope scans of HT-29 cells. Although inhibition of sEH in differentiated HT-29 and Caco2 cells led to an increase in sEH expression in both cell lines, this treatment had an opposite effect on CYP2J2 expression in HT-29 and Caco2 cells. In addition, tissue samples of colorectal carcinoma and adjacent normal tissues from 45 patients were immunostained for sEH and villin. We detected a significant decrease in the expression of both proteins in colorectal carcinoma in comparison to adjacent normal tissue, and the decrease in both sEH and villin expression revealed a moderate positive association. Taken together, our results showed that sEH is an important player in intestinal cell differentiation.

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In vitro and in silico investigation of anthocyanin derivatives as soluble epoxide hydrolase inhibitors

International Journal of Biological Macromolecules ◽

10.1016/j.ijbiomac.2018.02.061 ◽

2018 ◽

Vol 112 ◽

pp. 961-967 ◽

Cited By ~ 5

Author(s):

Jang Hoon Kim ◽

In Sook Cho ◽

Jaihyuk Ryu ◽

Ji Sun Lee ◽

Jong Seong Kang ◽

...

Keyword(s):

In Silico ◽

Epoxide Hydrolase ◽

Soluble Epoxide Hydrolase ◽

Soluble Epoxide Hydrolase Inhibitors

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Soluble Epoxide Hydrolase Deletion Attenuated Nicotine-induced Arterial Stiffness via Limiting the Loss of SIRT1

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00979.2020 ◽

2021 ◽

Author(s):

Shuiqing Hu ◽

Jinlan Luo ◽

Menglu Fu ◽

Liman Luo ◽

Yueting Cai ◽

...

Keyword(s):

Arterial Stiffness ◽

Vascular Remodeling ◽

Epoxide Hydrolase ◽

Vascular Dysfunction ◽

Soluble Epoxide Hydrolase ◽

Protective Effects ◽

Nicotine Treatment ◽

Beneficial Effects ◽

Sirt1 Inhibitor

Arterial stiffness, a consequence of smoking, is an underlying risk factor of cardiovascular diseases. Epoxyeicosatrienoic acids (EETs), hydrolyzed by soluble epoxide hydrolase (sEH), have beneficial effects against vascular dysfunction. However, the role of sEH knockout in nicotine-induced arterial stiffness was not characterized. We hypothesized that sEH knockout could prevent nicotine-induced arterial stiffness. In the present study, Ephx2 (the gene encodes sEH enzyme) null (Ephx2-/-) mice and wild-type (WT) littermate mice were infused with or without nicotine and administered with or without nicotinamide (NAM, SIRT1 inhibitor) simultaneously for four weeks. Nicotine treatment increased sEH expression and activity in the aortas of WT mice. Nicotine infusion significantly induced vascular remodeling, arterial stiffness, and SIRT1 deactivation in WT mice, which was attenuated in Ephx2-/- mice without NAM treatment. However, the arterial protective effects were gone in Ephx2-/- mice with NAM treatment. In vitro, 11,12-EET treatment attenuated nicotine-induced MMP2 upregulation via SIRT1-mediated YAP deacetylation. In conclusion, sEH knockout attenuated nicotine-induced arterial stiffness and vascular remodeling via SIRT1-induced YAP deacetylation.

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In vitro and in vivo Metabolism of a Potent Inhibitor of Soluble Epoxide Hydrolase, 1-(1-Propionylpiperidin-4-yl)-3-(4-(trifluoromethoxy)phenyl)urea

Frontiers in Pharmacology ◽

10.3389/fphar.2019.00464 ◽

2019 ◽

Vol 10 ◽

Cited By ~ 5

Author(s):

Debin Wan ◽

Jun Yang ◽

Cindy B. McReynolds ◽

Bogdan Barnych ◽

Karen M. Wagner ◽

...

Keyword(s):

Epoxide Hydrolase ◽

Potent Inhibitor ◽

Soluble Epoxide Hydrolase ◽

In Vivo Metabolism

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Inhibition of soluble epoxide hydrolase preserves cardiomyocytes: role of STAT3 signaling

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00533.2009 ◽

2010 ◽

Vol 298 (2) ◽

pp. H679-H687 ◽

Cited By ~ 26

Author(s):

Matthias J. Merkel ◽

Lijuan Liu ◽

Zhiping Cao ◽

William Packwood ◽

Jennifer Young ◽

...

Keyword(s):

Epoxide Hydrolase ◽

Glucose Deprivation ◽

Soluble Epoxide Hydrolase ◽

Nucleotide Polymorphisms ◽

Gene Encoding ◽

Mutant Proteins ◽

Stat3 Signaling ◽

Stat3 Inhibition

Soluble epoxide hydrolase (sEH) metabolizes epoxyeicosatrienoic acids (EETs), primarily 14,15-EET. EETs are derived from arachidonic acid via P-450 epoxygenases and are cardioprotective. We tested the hypothesis that sEH deficiency and pharmacological inhibition elicit tolerance to ischemia via EET-mediated STAT3 signaling in vitro and in vivo. In addition, the relevance of single nucleotide polymorphisms (SNPs) of EPHX2 (the gene encoding sEH) on tolerance to oxygen and glucose deprivation and reoxygenation and glucose repletion (OGD/RGR) was assessed in male C57BL\6J (WT) or sEH knockout (sEHKO) cardiomyocytes by using transactivator of transcription (TAT)-mediated transduction with sEH mutant proteins. Cell death and hydrolase activity was lower in Arg287Gln EPHX2 mutants vs. nontransduced controls. Excess 14,15-EET and SEH inhibition did not improve cell survival in Arg287Gln mutants. In WT cells, the putative EET receptor antagonist, 14,15-EEZE, abolished the effect of 14,15-EET and sEH inhibition. Cotreatment with 14,15-EET and SEH inhibition did not provide increased protection. In vitro, STAT3 inhibition blocked 14,15-EET cytoprotection, but not the effect of SEH inhibition. However, STAT3 small interfering RNA (siRNA) abolished cytoprotection by 14,15-EET and sEH inhibition, but cells pretreated with JAK2 siRNA remained protected. In vivo, STAT3 inhibition abolished 14,15-EET-mediated infarct size reduction. In summary, the Arg287Gln mutation is associated with improved tolerance against ischemia in vitro, and inhibition of sEH preserves cardiomyocyte viability following OGD/RGR via an EET-dependent mechanism. In vivo and in vitro, 14,15-EET-mediated protection is mediated in part by STAT3.

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